Cyclothiazide Prolongs Low [Mg2+]–Induced Seizure-Like Events

Abstract

Here we address the effects of cyclothiazide (CTZ), an allosteric inhibitor of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor desensitization, on low [Mg2+]–induced seizure-like events (SLEs) recorded from the CA3 pyramidal layer of juvenile rat hippocampal slices. CTZ (100 μM) made the period of tonic-like discharges (161 ± 18% of control) and the whole SLE (151 ± 15% of control) longer (in 7 of 9 slices) or induced endless SLE by stabilizing clonic-like bursting (in 2 of 9 slices). CTZ (30 μM) had no significant effects on SLE dynamics ( n = 4), whereas 300 μM CTZ induced endless SLEs in four of eight slices. Coapplication of CTZ (100 μM) with 100 μM GYKI-52466, the allosteric inhibitor of AMPA receptor function, restrained the effects of CTZ and shortened SLEs and their tonic phases to 37 ± 4.2 and 47 ± 4.2% of the control, respectively. Effects of GYKI-52466 and GYKI-52466 with CTZ on SLE dynamics were indistinguishable. 4-aminopyridine (4-AP; 50 μM) alone ( n = 5) or in combination with CTZ ( n = 6) transformed recurrent SLE pattern into incessant epileptiform activity with patterns distinguishable from those under 100 μM CTZ application. The effect of 4-AP may suggest a role for facilitated presynaptic glutamate release in disrupting recurrent dynamics. In contrast, the self-similar slow-down of low [Mg2+]–induced SLE dynamics by CTZ indicate AMPA receptor desensitization as a parameter shaping SLEs.